Study Finds Gene Variant That Might Confer Resistance to Alzheimer’s Disease

Several gene variants have been associated with risk of Alzheimer’s disease, with the best known being APOE3. Now, researchers with the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), have published research of a gene variant, APO3 Christchurch (APOE3ch), that appears to confer resistance to Alzheimer’s disease.

In their research, a woman was identified who carried a genetic variant that is known to cause early-onset Alzheimer’s. But she didn’t show any signs of the disease until her 70s, which was almost 30 years after her expected age of onset.

Fortunately, early-onset Alzheimer’s disease is rare, affecting less than 10% of all Alzheimer’s patients. Early-onset Alzheimer’s generally happens between the ages of 30 and mid-60s.

The woman in the study had two copies of the APOE3ch variant, which is named after Christchurch, New Zealand, where it was first identified. The woman in the study was in an extended family in Colombia with more than 6,000 living members. The family members who carry a rare gene mutation, Presenilin 1 (PSEN1) E280A, have a 99.9% risk of developing early-onset Alzheimer’s disease.

The woman in the study carried the PSEN1 E280A mutation, but also had two copies of APOE3ch. No other affected family member carried two copies of the APOE3ch variant.

Family members affected by the PSEN1 E280A mutations developed Alzheimer’s in their 40s. The woman with two copies of APOE3ch didn’t develop Alzheimer’s until her 70s.

Imaging studies showed she had only minor neurodegeneration, but did have large amounts of amyloid protein deposits, which have long been associated with the disease. However, the amount of tau tangles, another protein that is associated with thinking and memory issues in Alzheimer’s, was relatively low in the woman.

“Sometimes close analysis of a single case can lead to discovery that could have broad implications for the field,” said NIA director Richard J. Hodes. “We are encouraged that as part of our wide array of studies, this research in the unique genetic makeup of an exceptional individual can reveal helpful information.”

The research was published in the journal Nature Medicine.

The research was led by scientists at Massachusetts General Hospital, Boston, in collaboration with the University of Antioquia, Medellin, Colombia, Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, and Banner Alzheimer’s Institute, Phoenix.

In addition to the data analysis, the investigators ran experiments that indicated the APOE3ch variant may decrease the ability of APOE to bind to sugars called heparan sulphate proteoglycans (HSPG). APOE binding to HSPG has been identified as a possible mechanism that might contribute to amyloid and tau deposits.

The bottom line is the discovery might suggest new approaches to preventing and treating Alzheimer’s disease by developing drugs or gene therapies that interfere with APOE and HSPG binding.

In related Alzheimer’s news, a Chinese company, Shanghai Green Valley Pharmaceuticals, received conditional approval to treat Alzheimer’s disease in China for its Oligomannate (GV-971). China’s National Medical Products Administration (NMPA), the country’s equivalent of the U.S. Food and Drug Administration (FDA) approved Oligomannate for “mild to moderate Alzheimer’s disease (AD) and improving cognitive function.”

The drug is derived from seaweed. The company reported that its Phase III clinical trial was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 36-week study led by Peking Union Hospital and Shanghai Jiaotong University Medical School Mental Health Center. The trial was run at 34 Tier-1 hospitals across China on a total of 818 patients who had been diagnosed with mild to moderate Alzheimer’s disease. It was conducted in collaboration with IQVIA (formerly Quintiles) and Signant Health (formerly Bracket) and other partners.

Alzheimer’s experts and clinicians are hopeful, but skeptical of the study, which was not very long. Also, full data has not been published yet, and it’s not clear how the drug, which appears to affect the gut biome and reduce inflammation, actually works.

The company plans to launch a global Phase III clinical trial in 2020 in hopes of being able to file approval in other countries, including the United States.